Insomnia and anxiety are two conditions, which have substantial negative impact on day-to-day quality of life. Insomnia is often described as subjective complaint of poor sleep quality or quantity despite adequate time for sleep. Insomnia results in daytime fatigue, irritability and decreased concentration and is often associated with other diseases such as psychiatric disorders (e.g. anxiety conditions), medical disorders or substance abuse. Anxiety also leads to fatigue, irritability and decreased concentration. Several forms of anxiety are known, such as generalized anxiety disorder, panic disorder, social anxiety disorder and post-traumatic stress disorder. Effective treatment of said conditions thus positively influences day-to-day life of patients suffering from such conditions.
Current pharmaceuticals used for the treatment of insomnia and anxiety comprise benzodiazepines, benzodiazepine-receptor agonists, melatonin-receptor agonists as well as antidepressants. However, most of said drugs exhibit strong adverse effects such as addiction and substance abuse. Naturally-occurring and traditionally used pharmaceuticals comprise herbal substances such as valerenic acid. However, many patients describe their action as too weak to result in satisfying relief of the conditions outlined above.
GABAA receptors thus represent promising molecular targets for the treatment of inter alia insomnia and anxiety.
On a molecular level, it seems that herbal substances such as valerian extracts comprising valerenic acid target inter alia GABAA receptors. The pharmacological properties of GABAA receptors as well as their sensitivity to γ-aminobutyric acid (GABA) seem to be determined by the subunit composition. The completely assembled receptor is comprised of five subunits. Up to now, 19 isoforms of mammalian GABAA receptor subunits could be identified: α1-6, β1-3, γ1-3, δ, ε, π, ρ1-3 and θ, and it seems that most of the endogenous as well as exogenous ligands bind to interfaces between two of the subunits. GABAA receptors seem to be implicated in signaling processes involved in diseases such as insomnia and anxiety as already mentioned above, but also processes involved in pain, mood and panic disorders, epilepsy, schizophrenia and symptoms connected to alcohol and/or substance withdrawal/abuse. Therefore, compounds affecting GABAA receptors may not only be used for treating insomnia and anxiety disorders but possibly also for treating pain, mood and panic disorders, epilepsy, schizophrenia and symptoms connected to alcohol and/or substance withdrawal/abuse.
Furthermore, such compounds may be used for the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, depression, overdose with benzodiazepine drugs, enhancement of memory and alertness, Huntington's Chorea, muscular spasms and rigidity, sleep and seizure disorders, and withdrawal symptoms. Antagonists may be used, for example, to diagnose and treat Alzheimer's disease, Parkinson's disease and for enhancing cognition and reversing sedation after application of general anesthesia during surgery. Modulators can be useful in the prevention of anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; depression or bipolar disorders such as single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders; schizophrenia; attention deficit hyperactivity disorder and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work; convulsive or seizure disorders such as epilepsy and pain.
Modulators can be also used as general anaesthetics.
So far, no complete synthesis for making the natural compound valerenic acid or any derivatives thereof has been described. However, there have been attempts towards such a method as disclosed in Krishna, Rao G. S. Tetrahedron 1967, 23, 3215. However, the synthesis described therein does only provide for an epimere with the wrong configuration compared to natural valerenic acid (said structure is shown below in the detailed description of the invention). Further publications such as Bohlmann, F. and Lonitz, M. Chem. Ber. 1980, 113, 2410 and Baudouy, R. and Sartorette, J. Tetrahydron 1983, 39, 3293, are concerned with the synthesis of valerenal, but not with the synthesis of valerenic acid.
There is a need for alternative or improved compounds, which act as GABAA receptor ligands and thus may be used for the treatment of e.g. insomnia and anxiety. Furthermore, there is a need to provide a method or synthesis route which allows for making valerenic acid and valerenic acid derivatives and preferably is stereoselective.